In advanced melanoma of the limbs with in-transit metastasis, melphalan with isolated limb perfusion (M-ILP) produces around 50% complete remissions (CR). The combination of melphalan with tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) in isolated limb perfusion (TIM-ILP) gives around 80% CR. A prospective randomised phase II study compared 32 patients who received TIM-ILP with 32 patients who received TM-ILP (without IFNgamma). The overall remission rate (ORR) and the CR rate were superior with TIM-ILP as compared to TM-ILP, 100% vs. 91% and 78% vs. 69% respectively, but the differences are not significant. Given the efficacy of M-ILP on in-transit metastasis, the procedure was tested as an adjunct to surgery in high-risk (Breslow > or = 1.5 mm) primary melanoma of the limbs. Through the combined effort of the melanoma groups of the European Organization for Research and Treatment of Cancer (EORTC), the World Health Organization (WHO), and the North American Perfusion Group, 832 evaluable patients from 16 centres were entered in a phase III study. Median followup is 6.4 years. There was a trend for a longer disease-free interval after M-ILP. The difference is significant if the patients without elective lymph node dissection (ELND) are separately analysed, with a high significance in the 1.5 to 3 mm thickness subgroup. The occurrence of in-transit metastases was reduced from 6.6% to 3.3% by M-ILP. There was, however, no benefit of M-ILP in terms of survival. Prophylactic M-ILP cannot be recommended as a standard adjunct to surgery in high-risk primary limb melanoma. TIM-ILP or TM-ILP is a regional therapy with a very high regional response rate on melanoma in-transit metastasis.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Hyperthermic isolated limb perfusion for the treatment of soft tissue sarcomas.

Hyperthermic isolated limb perfusion (HILP) with various chemotherapeutic agents has been used for the local treatment of high-grade soft tissue sarcomas (STS) of the extremities, but in most cases, with a disappointing result. Most such regimens certainly should not be considered superior to surgery plus radiotherapy. Although the majority of extremity STS can be resected locally, some are very large and are in close proximity to bone, nerve or blood vessels. In these cases, amputation is the only means of resecting the tumour. A new combination of drugs used in the set-up of HILP with tumour necrosis factor-alpha and melphalan has emerged as a very promising option for the limb-saving management of locally advanced STS. In recent studies, complete response rates of approximately 30% and partial remission rates of 50% have been achieved, while the overall limb-salvage rate is more than 80%.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Toxicity and morbidity of isolated limb perfusion.

Because a relationship between toxicity and treatment outcome has never been demonstrated for isolated limb perfusion (ILP) with melphalan, it is important to keep the side-effects of the procedure restricted to a minimum. Risk factors for more severe acute regional toxicity have recently been identified with tissue temperature above 40 degrees C and a high melphalan peak concentration being the most important. Acute regional toxicity should be mild taking into account these factors and maintaining the normal physiological conditions in the limb during ILP. This should also decrease the incidence of long-term morbidity, especially ankle stiffness and muscle atrophy, since a relation between the severity of the acute regional tissue reactions and long-term morbidity has been demonstrated. Lymphedema is strongly linked to a concomitant regional lymph node dissection and this operation may be delayed until the acute regional tissue reactions have faded. It is not yet clear whether the addition of tumor necrosis factor-alpha (TNF-alpha) to melphalan increases regional toxicity. In the absence of melphalan leakage to the systemic circulation, systemic toxicity is minimal; this is also true with TNF-alpha. Compared to ILP with melphalan +/- TNF-alpha, ILP with other drugs is less effective and often is associated with increased regional toxicity.

Antineoplastic Agents, Alkylating↗

PubMedDate not supplied

Controversies concerning adjuvant regional isolated perfusion for stage I melanoma of the extremities.

The use of isolated perfusion with melphalan in an adjuvant setting for stage I extremity melanoma continues to be controversial. In this article, 2 retrospective studies compare patients undergoing perfusion from Groningen, the Netherlands, with matched controls from the Sydney Melanoma Unit in Australia and from 5 hospitals in the Netherlands and Westphalia (a region of Germany bordering the Netherlands). All patients underwent wide local excision for a primary extremity melanoma of 1.5 mm or more in thickness. In the first study, women with a melanoma of the leg (excluding the foot) and treated with perfusion had a significantly higher survival than women treated with local excision alone. In the second study, a proportional hazards regression analysis for recurrent disease and survival identified no statistically significant difference in favor of adjuvant perfusion. Two other studies from the literature evaluating the efficacy of perfusion are examined. Patients treated at the M.D. Anderson Cancer Center, Houston, with wide local excision and perfusion are compared retrospectively with a group of patients individually matched for prognostic factors from the University of Alabama in Birmingham, U.S.A. and the Sydney Melanoma Unit. A small subset of patients with tumors greater than 2 mm thick benefited from perfusion. A prospective randomized study from the University Hospital, Cologne, West Germany found benefits for all perfused patients with tumors greater than 1.5 mm but their patients did not appear to be individually matched for tumor thickness. It is concluded after critical appraisal of all these studies that there is insufficient convincing evidence to date of an advantage of perfusion over wide local excision alone.

Chemotherapy, Adjuvant↗

PubMedDate not supplied

Positive iliac and obturator nodes in melanoma: survival and prognostic factors.

BACKGROUND: The need for deep groin dissection when superficial nodes contain metastatic melanoma is controversial. METHODS: A review of 362 therapeutic groin dissections performed at our tertiary referral center between 1961 and 1995 revealed 71 patients (20%) with positive iliac and/or obturator nodes. This group was analyzed for survival rates, prognostic factors for survival, regional tumor control, and morbidity. RESULTS: Patients with involved deep nodes exhibited overall 5-year and 10-year survival rates of 24% (SE, 5%) and 20% (SE, 5%), respectively. Independent prognostic factors for survival were the number of positive iliac nodes (P = .0011), the Breslow thickness (P = .0069), and the site of the primary tumor (P = .0075). Patients with an unknown primary tumor seemed to have better prognoses. Seven patients (10%) experienced recurrence in the surgically treated groin. The short- and long-term morbidity rates (infection, 17%; skin flap necrosis, 15%; seroma, 17%; mild/ moderate lymphedema, 19%; severe lymphedema, 6%) compared well with those of other series studying inguinal as well as ilioinguinal dissections. CONCLUSIONS: From the present study it can be concluded that removal of deep lymph node metastases is worthwhile, because one of every five such patients survives for 10 years. Prognostic factors for survival are the number of involved iliac nodes, the Breslow thickness, and the site of the primary tumor. Long-term regional tumor control can be obtained for 90% of the patients. The morbidity of an additional deep lymph node dissection is acceptable.

Adolescent↗

PubMedDate not supplied

Modification of human tumour and normal tissue pH during hyperthermic and normothermic antiblastic regional isolation perfusion for malignant melanoma: a pilot study.

Human tumour and normal tissue pH were investigated during hyperthermic and normothermic antiblastic regional isolation perfusion and the effects of vascular occlusion, artificially induced hypoxia, hyperglycaemia, haemoglobin level of the perfusate and hyperthermia on tumour and normal tissue pH were evaluated. A pilot study was performed on 10 patients, with locally inoperable recurrent and primary malignant melanoma of the leg. The treatment consisted of a regional isolation perfusion with hyperthermia (120 min at 42-43 degrees C), at femoral level, followed by a normothermic regional isolation perfusion with Melphalan (60 min at 37-38 degrees C), at iliacal level, 7-10 can be distinguished: (1) first ischaemic anoxia period; (2) extracorporeal circulation, during which the leg is heated to the desired temperature, after which either hyperthermia or Melphalan is applied; (3) second ischaemic anoxia period. During the anoxia periods the large vessels that supply the leg are temporarily clamped and the effects on tissue pH can be investigated. During extracorporeal circulation, high-dose glucose can be administered to the isolated leg, to acutely decrease tumour tissue pH. Such a decrease is expected to sensitize tumours to hyperthermia, when applied immediately prior to or during heating. At the beginning of the treatment the mean tumour pH was significantly lower than normal tissue pH (7.14, with a mean tumour volume of 39.2 cm3, and 7.38, respectively; p < 0.01). During the perfusions with hyperthermia and Melphalan, tissue pH decreased by -0.41 units and -0.20 for tumour, and -0.11 units for normal tissue, respectively (all statistically significant). The two anoxia periods accounted for approximately half of the net decrease. During these periods tumour pH appeared to decrease more selectively, although there was great variation. The other investigated modalities, such as hyperglycaemia and hyperthermia, also decreased tissue pH, but to a lesser extent. However, a combination of more than one modality caused a larger decrease than a single one, but no preference for tumour could be detected. Before the second perfusion mean tumour pH was significantly increased by 0.14 units, and was no longer significantly different from normal tissue pH in the course of the regional isolation perfusion. This could be the reflection of the reduced tumour volume (by 30%, n.s.). Similar pH changes occurred during this Melphalan perfusion, but they were less pronounced since the total treatment time was shorter. Summarizing, tumour pH can be decreased more than normal tissue pH in the course of the regional isolation perfusion. In particular, vascular occlusion appeared to be tumour pH selective.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗

PubMedDate not supplied

Temporary vascular occlusion and glucose: effects on tumour and normal tissue pH in animal experiments.

The relationship between duration of a period of vascular occlusion and magnitude of pH decrease in tumour and normal tissue was investigated in rats. To acidify tissue pH further, moderate dose glucose (2.4-3.0 g.kg(-1).hr(-1)) was administered intravenously through a catheter positioned in a tail vein, immediately after the clamp was released. This sequence of pH modifying modalities was chosen since it is employed in clinical regional isolation perfusion for recurrence of malignant melanoma of the limbs. Tumour pH in rat rhabdomyosarcoma BA1112 decreased more than normal tissue pH under 10, 20, 30 or 60 min of temporary vascular occlusion. Administration of glucose following any period of clamping always decreased tumour pH further. The largest pH decrease (0.29 pH units) was obtained after 30 min of clamping followed by 60 min glucose and 60 min saline infusion. In the clinic the combination of a maximum of 30 min of clamping followed by moderate dose glucose infusion, which can decrease tumour pH effectively, can be easily achieved in the setting of regional isolation perfusion. It can be used for treatment modalities that are known to be enhanced at lowered tissue pH, such as hyperthermia and certain chemotherapeutic drugs. These results form the basis for studying the therapeutic gain which can be obtained with this model.

Animals↗

PubMedDate not supplied

Comparison between the use of whole blood versus a diluted perfusate in regional isolated perfusion by continuous monitoring of transcutaneous oxygen tension: a pilot study.

In 12 successive women (median age, 58 [39-89] years) who were treated with regional isolated perfusion for melanoma of the lower extremities, peroperative continuous monitoring of the transcutaneous oxygen tension (PtcO2) was performed as an indicator for tissue oxygenation and (sub)cutaneous perfusion. Regional perfusion started using whole blood as perfusate with a hematocrit of 40.7 +/- 4.9. After 40 min of drug circulation the perfusate was diluted to a hematocrit of 25.3 +/- 4.9, a value usually applied in perfusion. Flow rates (mean 51.2 +/- 14.4 mL/min/L perfused tissue) were kept at a level that caused no systemic leakage and no more than 10-cm increase above starting venous pressure. Oxygen supply was set at one half of the flow of the perfusate (in mL/min). The mean PtcO2 during the first part of perfusion, in which seven patients could achieve preperfusion levels for at least some of the time, was significantly higher than during the last part, in which no patient reached the preperfusion level (30.8 mm Hg vs 23.5 mm Hg; p = .0019). The mean maximal decrease in PtcO2 after dilution was 21.3 +/- 11.6 mm Hg. Venous blood gases of the perfusate also deteriorated after dilution. Two patients encountered a grade III and two a grade IV toxicity reaction after perfusion. We conclude that increasing the hematocrit of the perfusate to physiologic levels by using whole blood can guarantee a physiologic tissue oxygenation at relatively low flow rates. However, physiologic tissue oxygenation on its own is not enough to prevent toxicity after perfusion.

Adult↗

PubMedDate not supplied

Normothermic isolation perfusion with melphalan for advanced melanoma of the limbs.

Eighteen patients with advanced melanoma of the limbs underwent a single isolation perfusion with melphalan under normothermic conditions, i.e. tissue temperatures between 37.0 and 38.0 degrees C. There were no major complications. In 7 patients complete remission was achieved and in 8 the remission was partial, i.e. tumor reduction greater than 50%. No obvious response was seen in the remaining 3 patients. At the time of analysis 4 patients were still in complete remission, 56, 55, 19 and 8 months after perfusion, respectively. One patient died from distant spread, 17 months after perfusion, but without exhibiting new tumor growth in the perfused area. In 2 patients local control was transient with locally recurrent disease 28 and 10 months after perfusion, respectively. In patients with partial remission the duration of remission could not be determined because of supplementary treatment or death. Our results seem to be comparable to those obtained by so-called mild hyperthermic perfusions.

Chemotherapy, Cancer, Regional Perfusion↗